Medical treatments based on anamorelin

ABSTRACT

Methods of treating cancer related conditions using anamorelin are described.

FIELD OF THE INVENTION

This invention relates to pharmaceutical treatments using anamorelin,and relates particularly to the treatment of conditions and disordersassociated with cancer cachexia.

BACKGROUND

Cancer cachexia, often referred to as cancer anorexia-cachexia syndrome(CACS), is a multifactorial condition with a high prevalence innon-small cell lung cancer (NSCLC). Cancer cachexia is characterized bydecreased body weight (mainly lean body mass; LBM), and is associatedwith worsened morbidity and survival. Standard effective treatments arelacking, although anamorelin has shown promise as a treatment in thisfield. Anamorelin is a novel, selective ghrelin receptor agonist withappetite-enhancing and anabolic activity.

A standard off-label therapy for cancer cachexia is megestrol acetate,which is approved to increase appetite and prevent weight loss inpatients with AIDS. However, megestrol has only been shown to increasebody weight and water in patients, and does not improve fat mass or leanbody mass.

Megestrol acetate also has not been shown to improve quality of life incancer cachexia patients. Lesniak et al. conducted a systematic reviewof clinical trials with megestrol acetate, and reported: “Based on asystematic review of trials with megesterol acetate in patients withcancer anorexia-cachexia syndrome, quality of life was measured usingdifferent scales in 14 studies, and in 13 of the 14 studies, there wasno significant difference between patients receiving megesterol acetateand those taking placebo, dronabinol, eicosapentaenoic acid orglucocorticosteroids.” Leśniak W1, Bala M, Jaeschke R, Krzakowski M.,Effects of megestrol acetate in patients with cancer anorexia-cachexiasyndrome—a systematic review and meta-analysis. Pol Arch Med Wewn. 2008November; 118(11):636-44.

Other drugs have also failed to improve the quality of life in cancercachexia patients. Del Fabbro reported a double-blind placebo-controlledtrial and the effect of melatonin on appetite and other symptoms inpatients with advanced cancer and cachexia. No differences betweenmelatonin and placebo groups after 4 weeks were observed regardingweight, body composition (including fat-free mass), symptom scores, andquality-of-life outcomes (as measured by FACIT-F and FAACT). Del FabbroE1, Dev R, Hui D, Palmer L, Bruera E. Effects of melatonin on appetiteand other symptoms in patients with advanced cancer and cachexia: adouble-blind placebo-controlled trial. J Clin Oncol. 2013 Apr. 1;31(10):1271-6.

Enobosarm((2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide)(also known as Ostarine, GTx-024 and MK-2866) is an investigationalselective androgen receptor modulator (SARM) under development forconditions such as muscle wasting and osteoporosis. Dobs et al. reportphase 2 data that includes some quality of life data as measured byFAACT/FACIT-F, but it only compares the measurements to baseline withintreatment arms rather than assessing active versus placebo, renderingany conclusions difficult to reach. Dobs AS et al., Effects of enobosarmon muscle wasting and physical function in patients with cancer: adouble-blind, randomised controlled phase 2 trial. Dobs AS et al.,www.thelancet.com/oncology Published online Mar. 14, 2013http://dx.doi.org/10.1016/S1470-2045(13)70055-X.

Garcia and Polvino performed a Phase I study (single-center, randomized,double-blind, and placebo-controlled) in which healthy subjects weredivided into three dosage groups. Garcia, J. M., Polvino, W. J. Effecton body weight and safety of RC-1291, a novel, orally available ghrelinmimetic and growth hormone secretagogue: results of a phase I,randomized, placebo-controlled, multiple-dose study in healthyvolunteers, Oncologist, 2007; 12:594-500. The first group receivedplacebo or 25 mg anamorelin once per day, for 5 days. The second groupreceived anamorelin at either 25 mg twice per day or 50 mg once per dayfor 6 days, and then crossed over to the other dosage regimen for 5days; three subjects in this group received placebo for all 11 doses tomaintain double-blinding. The third group received placebo or 75 mganamorelin once per day for 6 days. Subjects who received anamorelin ateither 50 or 75 mg doses had significant dose-related weight gain after6 days versus placebo, with the greatest increases seen with dailydosing. The mean increase in body weight from baseline after 50 mg (oncedaily dose or split-dose regimen) or 75 mg anamorelin once per day wassignificant relative to placebo.

A follow-up study by Garcia and Polvino characterized the effects ofanamorelin on growth hormone (GH) levels in healthy subjects, as well asits effects on insulin-like growth factor 1 (IGF-1), insulin-like growthfactor binding protein 3 (IGFBP-3), serum hormone profiles, andcarbohydrate metabolism. Garcia, J. M., Polvino, W. J. Pharmacodynamichormonal effects of anamorelin, a novel oral ghrelin mimetic and growthhormone secretagogue in healthy volunteers, Growth Horm IGF Res, 2009;19:267-73. This study (single-center, randomized, double-blind, andplacebo-controlled) used the same dosage groups as the previous study(i.e., one group received placebo or a single dose of 25 mg anamorelinonce per day, the second group received placebo or either 25 mganamorelin twice per day or 50 mg anamorelin once per day for 6 days,and then switched to the other dosage regimen for 5 days, and the thirdgroup received placebo or 75 mg anamorelin once per day). All doses ofanamorelin significantly increased GH and IGF-1 levels, particularly the50 mg single dose and 75 mg dose; the split 50 mg dose showed anincrease in GH and IGF-1 levels, but not to the same degree as thesingle 50 mg dose. Again, significant increases in body weight were seenin groups receiving the 50 mg dose (single or split dose) and 75 mgdose. Increases in body weight correlated strongly with increases inIGF-1 levels.

Garcia et al then performed a pilot study (multicenter, randomized,double-blind, placebo-controlled, crossover study) of anamorelintreatment in patients with various cancers and cachexia who had aninvoluntary body weight loss of over 5% in the previous 6 months, anestimated life expectancy of over 3 months, and an Eastern CooperativeOncology Group (ECOG) performance status of 0-2. Garcia, J. M., Friend,J., Allen, S. Therapeutic potential of anamorelin, a novel, oral ghrelinmimetic, in patients with cancer-related cachexia: a multicenter,randomized, double-blind, crossover, pilot study, Support Care Cancer,2013; 21:129-37. A single dose of 50 mg anamorelin or placebo was givenonce per day over the course of the study, followed by a 3 to 7-daywashout period, and then treatments were switched. Study assessmentsincluded body weight, appetite, food intake, growth hormone (GH) levels,and patient-reported symptom assessment (as measured by the AndersonSymptom Assessment Scale (ASAS), the Functional Assessment of ChronicIllness Therapy With Additional Fatigue Domain (FACIT-F), and theBristol-Myers Anorexia/Cachexia Recovery Instrument, 7-question version(BACRI-7)). Anamorelin significantly increased body weight compared withplacebo. GH, IGF-1, and IGFBP-3 levels also significantly increased withanamorelin, particularly in terms of the mean serum concentrations ofthe hormones. Food intake increased but not significantly.Patient-reported appetite significantly improved with anamorelin asmeasured by ASAS; as measured by BACRI-7, there was no significantdifference in appetite among treatment groups although significantlymore patients reported greater enjoyment from eating while on anamorelintherapy. Anamorelin treatment also significantly increased FACIT-Fscores.

Garcia et al performed a phase II trial (multicenter, randomized,double-blind, and placebo-controlled) lasting 12 weeks and including 81patients with various cancers with cachexia (body weight loss of over 5%within the previous 6 months), and an ECOG score of 0-2. Garcia, J.,Boccia, R. V., Graham, C., Kumor, K., Polvino, W. A phase II randomized,placebo-controlled, double-blind study of the efficacy and safety ofRC-1291 (RC) for the treatment of cancer cachexia, J Clin Oncol, 2007;25:18(S):9133. Patients received either 50 mg anamorelin once per day orplacebo during the 12-week study, and quality of life (FACIT-F), weightgain, IGF-1 and IGFBP-3 were measured over the course of the trial.Total and lean body mass significantly increased as compared to placeboat weeks 4 and 8; the magnitude of the increase was stable from weeks 4to 12 for both total and lean body mass. Fat mass decreased more inplacebo-treated patients than in anamorelin-treated patients, althoughthe difference did not reach statistical significance. SeeWO/2008/124183 of Mann and Polvino. Interestingly, no correspondingincrease in scale weight measures was noted. Levels of IGF-1 and IGFBP-3were significantly increased at weeks 4, 8, and 12. No significanteffects on quality of life as measured by the FACIT-F test were noted.However, ASAS scores were improved. See WO/2008/124183 of Mann andPolvino.

Temel et al conducted a phase II study (multicenter, randomized,double-blind, and placebo-controlled) lasting 12 weeks in 226 patientswith advanced non-small cell lung cancer (NSCLC) and an ECOG score 0-1who were candidates for treatment with carboplatin/paclitaxel (with orwithout bevacizumab). Temel J. B., S; Jain, M et al. Efficacy and safetyof anamorelin HCl in NSCLC patients: results from a randomized,double-blind, placebo-controlled, multicenter phase II study, Presentedat the European Cancer Congress, 27 Sept.-1 Oct. 2013, Amsterdam,Netherlands; Abstract no 1308. Patients were given once daily doses of50 or 100 mg anamorelin or matching placebo, and weight gain and IGFBP-3levels were measured over the course of the study. The group receiving100 mg anamorelin had a statistically significant average weight gainfrom baseline to week 12. Anamorelin therapy led to statisticallysignificant increases in IGFBP-3 as compared to placebo. Anamorelin alsoimproved patient scores on the MD Anderson Symptom Inventory (MDASI),which measures the severity of symptoms on daily functioning amongcancer patients, although the improvement was not significant.

A Study of anamorelin in NSCLC, presented at ASCO Quality Care 2013,included results of individual MDASI questions, including the responseon fatigue. This study was only in NSCLC patients, not in NSCLC patientssuffering from cachexia.http://meetinglibrary.asco.org/content/119980-140

U.S. Pat. No. 6,303,620 discloses the use of novel compounds includinganamorelin for: reducing cachexia due to cancer; treating anorexia;regulating food intake; improving muscle strength; treating chronic oracute fatigue syndrome and insulin resistance; treating conditions whichrequire increased plasma GH levels; treating immunosuppressed patients;and treating cardiomyopathy, cardiac failure, impaired cardiac function,and myocardial infarction.

U.S. Pat. No. 7,994,329 discloses the use of agonists of growth hormonesecretagogue receptor type 1A (GHSR 1A) for use in medicaments for theregulation of food intake, body mass index (BMI), and the treatment ofanorexia, type II diabetes and wasting associated with various diseasesand conditions.

U.S. Pat. No. 8,394,833 discloses the use of anamorelin for reducingnausea, treating emesis and also evaluated quality of life as measuredby the ASAS (rating of the severity from 1-10 of the following symptoms:pain, fatigue, nausea, depression, anxiety, drowsiness, shortness ofbreath, appetite, sleep and feeling of well-being) and the use of growthhormone secretagogues for increasing appetite and body weight and IGF-1levels.

U.S. Pub. No. 2005/0261201 discloses the use of a growth hormonesecretagogue for reducing C-reactive protein in a patient suffering fromcachexia, anorexia, chronic fatigue syndrome, diabetes, and tumormetastasis as well as inducing secretion of GH and IGF-1, and its use intreating a patient who has had or who is at risk of a vascular eventsuch as myocardial infarction.

WO/2013/158874 discloses the use of anamorelin HCl for the treatment ofcancer-related cachexia and conditions which require increased plasma GHlevels, and the use of growth hormone secretagogues for increasingappetite and body weight.

None of these patent publications discloses the use of anamorelin totreat early satiety or fatigue resulting from cachexia, or forincreasing survival time of terminally ill cancer patients. They also donot disclose improvement of patient quality of life as measured by theanorexia/cachexia domain of the Functional Assessment ofAnorexia/Cachexia Therapy (FAACT) assessment, which measures physicaland functional well-being as well as specific concerns related toanorexia and cachexia by asking questions directed to body weight/image,appetite, food consumption, vomiting, early satiety, and stomach pain.

SUMMARY OF THE INVENTION

The inventors have developed several methods for treating disorders andconditions associated with cancer cachexia using anamorelin. A firstprincipal embodiment relates to the unique condition of patientsdefining this condition, and the surprising ability of anamorelin toincrease lean body mass in this population. In this embodiment theinvention provides a method of treating cachexia in a human cancerpatient, comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime.

In another embodiment the invention provides a method of treatingcachexia in certain well-defined patient groups, such as a human cancerpatient suffering from unresectable Stage III or IV non-small cell lungcancer and cachexia as defined by body weight loss greater than or equalto 5% in the previous 6 months or body mass index less than 20 kg/m², byincreasing the lean body mass of said patient, comprising administeringto said patient a therapeutically effective amount of anamorelin for atherapeutically effective period of time.

Another embodiment relates to the unexpected ability of anamorelin todefeat the early satiety that commonly occurs in cancer cachexia andother related conditions. In this embodiment the invention provides amethod of treating early satiety resulting from cancer cachexia in ahuman cancer patient comprising administering to said patient atherapeutically effective amount of anamorelin for a therapeuticallyeffective period of time.

A fourth principal embodiment relates to the unexpected ability ofanamorelin to treat the fatigue that is often associated with cancer andcancer treatments. In this embodiment the invention provides a method oftreating fatigue resulting from cancer cachexia in a human cancerpatient comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime.

A fifth principal embodiment relates to the use of anamorelin toincrease the survival time of cancer patients. In this embodiment theinvention provides a method of increasing the survival time of aterminally ill cancer patient comprising administering to said patient atherapeutically effective amount of anamorelin for a therapeuticallyeffective period of time.

A sixth principal embodiment relates to the use of anamorelin to improvespecific quality of life measures in cancer cachexia patients. In thisembodiment the invention provides a method of improving quality of lifeas measured by FAACT in the anorexia/cachexia domain in a human cancerpatient comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime.

A seventh principal embodiment relates to the use of anamorelin toimprove different measures of body mass. In this embodiment theinvention provides a method of increasing total body mass, lean bodymass, and fat mass in a human patient suffering from cancer cachexiacomprising administering to said patient a therapeutically effectiveamount of anamorelin for a therapeutically effective period of time. Theincrease in fat mass is particularly beneficial because it reflects anincrease in stored energy in these frequently weak and malnourishedpatients.

An eighth principal embodiment relates to the use of anamorelin toimprove other quality of life measures in cancer cachexia patients. Inthis embodiment, the invention provides a method of improving quality oflife in a human cancer patient comprising administering to said patienta therapeutically effective amount of anamorelin for a therapeuticallyeffective period of time, wherein the quality of life improvement ismeasured by:

-   -   FAACT (Total Score or TOI);    -   SEA Score;    -   SEF Score;    -   FACIT-G (Total Score or TOI); or    -   FACIT-F (Total Score or TOI).

In any of the foregoing principal embodiments, the administration ispreferably oral. In addition, the administration is preferably done on aonce-daily basis. Additional advantages of the invention are set forthin part in the description that follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The advantages of the invention will be realized and attained by meansof the elements and combinations particularly pointed out in theappended claims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graphical representation of the primary efficacy outcome(lean body mass) in terms of the median change from baseline in theintent to treat (“ITT”) population, for patients receiving anamorelinand placebo (PBO) in Romana 1. Data shown are observed values only(i.e., no modeling or imputation for missing data).

FIGS. 2A-B are graphical representations of patient symptoms andconcerns related to cachexia as measured by change in FAACTanorexia/cachexia subscore and SEA score, specifically the treatmentcomparison of change from baseline at each visit in the modified intentto treat (“MITT”) population in patients receiving anamorelin andplacebo in Romana 1. Data shown are from a mixed-effects pattern-mixturemodel.

FIGS. 3A-B are graphical representations of patient symptoms andconcerns related to fatigue as measured by change in FACIT-F fatiguesubscore and SEF score, specifically the treatment comparison of changefrom baseline at each visit in the MITT population in patients receivinganamorelin and placebo in Romana 1. Data shown are from a mixed-effectspattern-mixture model.

FIG. 4 is a graphical representation of the change from baseline overtime in body weight in the MITT population, including the statisticalsignificance of any differences in results from patients treated withplacebo vs. anamorelin. Data shown are from a mixed-effectspattern-mixture model.

FIGS. 5A-B are graphical representations of health-related Quality ofLife changes from baseline in FAACT Total and TOI (Total Outcome Index)in the MITT population in Romana 1. Data shown are from a mixed-effectspattern-mixture model.

FIGS. 6A-B are graphical representations of health-related Quality ofLife change from baseline in FACIT Total and TOI (Total Outcome Index)in the MITT population in Romana 1. Data shown are from a mixed-effectspattern-mixture model.

FIG. 7 is a graphical representation of the primary efficacy outcome(lean body mass) in terms of the median change from baseline in the ITTpopulation, for patients receiving anamorelin and placebo (PBO) inRomana 2. Data shown are observed values only (i.e., no modeling orimputation for missing data).

FIGS. 8A-B are graphical representations of patient symptoms andconcerns related to cachexia as measured by change in FAACTanorexia/cachexia subscore and SEA score, specifically the treatmentcomparison of change from baseline at each visit in the MITT populationin patients receiving anamorelin and placebo in Romana 2. Data shown arefrom a mixed-effects pattern-mixture model.

FIGS. 9A-B are graphical representations of patient symptoms andconcerns related to fatigue as measured by change in FACIT-F fatiguesubscore and SEF score, specifically the treatment comparison of changefrom baseline at each visit in the MITT population in patients receivinganamorelin and placebo in Romana 2. Data shown are from a mixed-effectspattern-mixture model.

FIGS. 10A-D are graphical representations of the results for the FatigueDomain of FACIT-F assessment over the 12-week study period in specificsubgroups of MITT patients in Romana 2. Data shown are from amixed-effects pattern-mixture model.

FIG. 11 is a graphical representation of the change from baseline inbody weight of the MITT population over the course of the study, alongwith the statistical significance of the change (p-values).

FIGS. 12A-B are bar graphs depicting the effect of administering 100 mganamorelin daily for 12 consecutive weeks versus placebo in two separateblinded placebo controlled trials on total body mass, lean body mass,fat mass and bone mass in cancer patients (median change from baseline),in Romana 1 (12A) and Romana 2 (12B).

FIGS. 13A and 13B show the change from baseline over time in individualquestions from the FAACT, early satiety, in Romana 1 and 2,respectively.

DETAILED DESCRIPTION

Definition and Use of Terms

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon.

When the singular forms “a,” “an” and “the” or like terms are usedherein, they will be understood to include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “ahydrocarbon” includes mixtures of two or more such hydrocarbons, and thelike. The word “or” or like terms as used herein means any one member ofa particular list and also includes any combination of members of thatlist.

When used herein the term “about” or “ca.” will compensate forvariability allowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in product strength andbioavailability due to manufacturing variations and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredpharmaceutically equivalent or bioequivalent, or both if the contextrequires, to the recited strength of a claimed product. It will beunderstood that all numeric values expressed in this document can beprefaced by the term “about.”

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.

When a range of values can be used to describe a particular regimen, itwill be understood that the range can be defined by selectivelycombining any one of the lower end of variables described in thespecification with any one of the upper end of variables described inthe specification that is mathematically possible.

Throughout this application, whenever a standard is given with referenceto a test or methodology currently accepted and applied in thescientific community, the standard will be understood to be evaluatedwith respect to the test or methodology as it is reported in thepublished literature on Jul. 1, 2014.

The terms “treating” and “treatment,” when used herein, refer to themedical management of a patient with the intent to cure, ameliorate,stabilize, or prevent a disease, pathological condition, or disorder.This term includes active treatment, that is, treatment directedspecifically toward the improvement of a disease, pathologicalcondition, or disorder, and also includes causal treatment, that is,treatment directed toward removal of the cause of the associateddisease, pathological condition, or disorder. In addition, this termincludes palliative treatment, that is, treatment designed for therelief of symptoms rather than the curing of the disease, pathologicalcondition, or disorder; preventative treatment, that is, treatmentdirected to minimizing or partially or completely inhibiting thedevelopment of the associated disease, pathological condition, ordisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe associated disease, pathological condition, or disorder.

As used herein, the term “significantly” refers to a level ofstatistical significance. The level of statistical significant can be,for example, of at least p<0.05, of at least p<0.01, of at leastp<0.005, or of at least p<0.001. Unless otherwise specified, the levelof statistical significance when recited is p<0.05. When a measurableresult or effect is expressed or identified herein, it will beunderstood that the result or effect is preferably evaluated based uponits statistical significance relative to a baseline. In like manner,when a treatment is described herein, it will be understood that thetreatment preferably shows efficacy to a degree of statisticalsignificance.

As used herein, “therapeutically effective amount” refers to an amountsufficient to elicit the desired biological response. Thetherapeutically effective amount or dose will depend on the age, sex andweight of the patient, and the current medical condition of the patient.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors in addition to the presentdisclosure.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.“Pharmaceutically acceptable salts” means salts that arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity.

When a weight of an active ingredient is given without reference to thefree base or salt of the active ingredient, it will be understood thatthe weight can refer to the weight of the free base of the weight or theentire salt.

“Cachexia” can be defined by a variety of methods in any of theprincipal embodiments or subembodiments of the present invention. Inparticular, and of the following definitions can be used:

-   -   a clinical syndrome characterised by one or a combination of        anorexia, early satiety, weight loss, muscle wasting, anemia,        and oedema, but is preferably defined by 3, 4, 5 or all of these        conditions.    -   body weight loss greater than or equal to 5% in the previous 6        months and/or body mass index less than 20 kg/m².    -   body weight loss greater than 2% in the previous 3 or 6 months        with a BMI<20    -   body weight loss >2% in the previous 3 or 6 months with an        appendicular skeletal muscle index consistent with sarcopenia        (males <7.26 kg/m²; females <5.45 kg/m²)    -   a multifactorial syndrome characterized by severe body weight,        fat and muscle loss and increased protein catabolism due to        underlying disease(s).

Early satiety refers to the tendency of a patient to experience fullnessor satiety early when consuming a meal.

Fatigue is generally defined as a feeling of weariness, tiredness, orlack of energy. Fatigue can also be defined in terms of patient scoreson various assessments or self-evaluations including questions designedto rank feelings of weariness, tiredness, or lack of energy. Specificassessments include the FACIT-F, which contains a 27-item FunctionalAssessment of Cancer Therapy—General (FACT-G) and a Fatigue Subscale(also referred to herein as the “fatigue domain”) consisting of thirteenquestions that can be scored 0-4 and measure the patient's perception offatigue and anemia-related concerns. The FACIT-F and FACT-Gquestionnaires are described in: The Functional Assessment of ChronicIllness Therapy (FACIT) Measurement System: properties, applications,and interpretation by Webster, K, Cella, D, and Yost, K, Health andQuality of Life Outcomes, volume 1, published 2003; Manir, Indian JPalliat Care. 2012 May-August; 18(2): 109-116; and Minton O, Stone P. Asystematic review of the scales used for the measurement ofcancer-related fatigue (CRF) Ann Oncol. 2009; 20:17-25. An increase inthe patient's score during the course of the therapy indicates animprovement in fatigue.

As reported by Manir et al., FACIT-F scoring is a quality of lifeassessment tool used to assess cancer treatment related fatigue. CellaDF. Manual of the functional assessment of chronic illness therapy(FACIT) scales.Version 4.Evanston, Ill.: Evanston NorthwesternHealthcare. 1997. It has good test-retest reliability (r ranging from0.82 to 0.92) and is sensitive to change over time. It has also beenshown to have convergent and discriminate validity. Cella DF. Manual ofthe functional assessment of chronic illness therapy (FACIT)scales.Version 4.Evanston, Ill: Evanston Northwestern Healthcare. 1997;Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuringfatigue and other anemia-related symptoms with the Functional Assessmentof Cancer Therapy (FACT) measurement system. J Pain Symptom Manage.1997; 13:63-74. [PubMed: 9095563]; Cella D F, Bonomi A E, Leslie W T,Von Roenn J, Tchekmeydian N S. Quality of life and nutritionalwellbeing, Measurements and relationship. Oncology. 1993;79(suppl):105-11.

FACIT-F (version 4) is a 40-item self-report instrument. It includescore Functional Assessment of Cancer Therapy—General (FACT-G) scale with27 items and one additional concern subscale (Fatigue) with 13 items.FACT-G items are divided into four subscale items: (a) PhysicalWell-being (PWB) (7 items), (b)Social/Family Well-being (SWB)(7 items),(c) Emotional Well-being (EWB) (6 items), and (d) Functional Well-being(FWB) (7 items). FACIT-F scores use a 5-point Likert-type score rangingfrom “0”(Not at all) to “4” (Very much).

Scores are obtained in each of the special domains and FACT-G score(includes summed score of PWB, SWB, EWB, and FWB). Total FACIT score wasobtained by adding additional concern score (Fatigue) with FACT-G.Negatively stated items are reversed by subtracting the response from“4.” After reversing proper items, all subscale items are summed to atotal, which is the subscale score. For all FACIT scales and symptomindices, the higher the score, the better the Health-related Quality ofLife (HRQoL). For missing and unanswered items, subscale scores areprorated as per administration guideline manual of FACIT-F score. Thisis usually done by using the formula below:Prorated subscale score=[Sum of item scores]×[N of items in subscale]÷[Nof items answered].

When there are missing data, prorating subscale score in this way isacceptable as long as more than 50% of the items were answered (e.g. aminimum of 4 of 7 items, 4 of 6 items, etc.). The total score is thencalculated as the sum of the unweighted subscale scores. The FACT scaleis considered to be an acceptable indicator of patient quality of lifeas long as the overall item response rate is greater than 80% (e.g. atleast 22 of 27 FACT-G items completed).

The prevalence of fatigue at each measurement point is determined bychoosing a cut-off score of <34 in the FACIT-F (additional concernitem). Minton O, Stone P. A systematic review of the scales used for themeasurement of cancer-related fatigue (CRF) Ann Oncol. 2009; 20:17-25.[PubMed: 18678767]

A four question subset of the Fatigue Subscale, called the SimplifiedEvaluation for Fatigue (SEF), is also used to determine if the patientis suffering from fatigue, again ranked from 0-4, with questionsspecifically directed to being too tired to eat, feeling fatigued orweak all over, and being forced to spend time in bed. An increase in thepatient's score during the course of the therapy, preferably of at leastabout 1.0, 1.25, 1.50, 1.75, or 2.0 points from baseline, indicates animprovement in fatigue.

FACT-G includes 4 domains: physical well-being (PWB, seven items),social/family well-being (SWB, seven items), emotional well-being (EWB,six items), and functional well-being (FWB, seven items), which can bescored 0-4. PWB questions are directed to energy levels, nausea, pain,problems with side effects, and feeling ill. SWB questions are directedto social and emotional support from friends, family, and the patient'spartner. EWB questions are directed to feelings of sadness, hopelessnessand nervousness and concerns about dying and worsening condition. FWBquestions are directed to ability to work and enjoy life, ability tosleep, and overall quality of life.

Increasing the survival time refers to increasing the longevity of apatient. FAACT refers to Functional Assessment of Anorexia CachexiaTherapy (FAACT) Questionnaire. The FAACT Questionnaire is described in:Quality of Life and Nutrition in the Patient with Cancer by Small, W,Carrara, R., Danford, L, Logemann, J, and Cella, D, ACCC's “IntegratingNutrition Into Your Cancer Program, pages 13-14, published March/April2002. FAACT in the anorexia/cachexia domain refers to the followingseries of twelve questions that measure patients' perception of andconcerns related to appetite, food consumption, weight gain/loss,vomiting, and stomach pain, which can be scored from 0-4.

Not A Some- Quite Very ADDITIONAL CONCERNS at all little what a bit muchI have a good appetite 0 1 2 3 4 The amount I eat is sufficient 0 1 2 34 to meet my needs I am worried about my weight 0 1 2 3 4 Most foodtastes unpleasant to me 0 1 2 3 4 I am concerned about how thin 0 1 2 34 I look My interest in food drops as soon 0 1 2 3 4 as I try to eat Ihave difficulty eating rich or 0 1 2 3 4 “heavy” foods My family orfriends are 0 1 2 3 4 pressuring me to eat I have been vomiting 0 1 2 34 When I eat, I seem to get full 0 1 2 3 4 quickly I have pain in mystomach area 0 1 2 3 4 My general health is improving 0 1 2 3 4

A score of 18, 19, 20, 21, 22, 23, 24 or 25 or higher on the FAACTanorexia/cachexia domain can be used to indicate that the patient issuffering from anorexia and/or cachexia; an increase in the patient'sscore during the course of the therapy, preferably of 2, 3, 4, 5 or morefrom baseline, indicates an improvement in cachexia. A four-questionsubset of the FAACT, called the Simplified Evaluation for Appetite(SEA), is also used to measure appetite/eating, again ranking questionsfrom 0-4, with questions specifically directed to appetite, sufficiencyof food consumption, pressure by others to eat, and feelings of earlysatiety, or getting full quickly after starting to eat. An increase inthe patient's score during the course of the therapy of at least about1.0, 1.25, 1.50, 1.75, or 2.0 points from baseline, indicates animprovement in appetite.

FAACT total score refers to the patient's score on the FACT-G added tohis score on the FAACT anorexia/cachexia subscale. A FAACT total scoreof 21, 22, 23, 24, 25, or 26 or higher indicates that the patient hascachexia; an increase in the patient's score during the course of thetherapy, preferably of 3, 4, 5 or more from baseline, indicates animprovement in cachexia.

FAACT Trial Outcome Index (TOI) refers to the patient's score on the PWBand FWB subsections of the FACT-G added to his score on the FAACTanorexia/cachexia subscale. A FAACT TOI of greater than 16, 18, 20, 22,or 24 indicates that the patient has cachexia; an increase in thepatient's score during the course of the therapy, preferably of 3, 4, 5or more from baseline, indicates an improvement in cachexia.

FACIT-F total score refers to the patient's score on the FACT-G added tohis score on the Fatigue Subscale of the FACIT-F. A FACIT-F total scoreof 16, 18, 20, 22 or 24 or higher indicates that the patient hasfatigue; an increase in the patient's score during the course of thetherapy, preferably of 3, 4, 5 or more from baseline, indicates animprovement in fatigue.

FACIT-F TOI refers to the patient's score on the PWB and FWB subsectionsof the FACT-G added to his score on the Fatigue Subscale of the FACIT-F.A FACIT-F TOI of 16, 18, 20, 22 or 24 or higher indicates that thepatient has fatigue; an increase in the patient's score during thecourse of the therapy, preferably of 3, 4, 5 or more from baseline,indicates an improvement in fatigue.

Stage III non-small cell lung cancer includes both Stage IIIA and IIIBas defined by the National Cancer Institute at the National Institutesof Health. Stage IV NSCLC is also defined by the National CancerInstitute at the National Institutes of Health. Criteria for stagingNSCLC can be found at National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: Non-small cell lung cancer.Version 2.2013. Available athttp://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. AccessedSep. 24, 2013.

ECOG (Eastern Cooperative Oncology Group) Status refers to scales andcriteria used by doctors and researchers to assess how a patient'sdisease is progressing, assess how the disease affects the daily livingabilities of the patient, and determine appropriate treatment andprognosis.

ECOG PERFORMANCE STATUS* Grade ECOG 0 Fully active, able to carry on allpre-disease performance without restriction 1 Restricted in physicallystrenuous activity but ambulatory and able to carry out work of a lightor sedentary nature, e.g., light house work, office work 2 Ambulatoryand capable of all self care but unable to carry out any workactivities. Up and about more than 50% of waking hours 3 Capable of onlylimited self care, confined to bed or chair more than 50% of wakinghours 4 Completely disabled. Cannot carry on any self care. Totallyconfined to bed or chair 5 Dead *Oken, M. M., Creech, R. H., Tormey, D.C., Horton, J., Davis, T. E., McFadden, E. T., Carbone, P. P.: ToxicityAnd Response Criteria Of The Eastern Cooperative Oncology Group. Am JClin Oncol 5: 649-555, 1982.Discussion

As mentioned above, the inventors have developed several methods fortreating disorders and conditions associated with cancer cachexia usinganamorelin. In a first principal embodiment, the invention provides amethod of treating cachexia in a human cancer patient by increasing thelean body mass of said patient, comprising administering to said patienta therapeutically effective amount of anamorelin for a therapeuticallyeffective period of time.

In a second principal embodiment, the invention provides a method oftreating cachexia in a human cancer patient suffering from unresectableStage III or IV non-small cell lung cancer and cachexia as defined bybody weight loss greater than or equal to 5% in the previous 6 months orbody mass index less than 20 kg/m², by increasing the lean body mass ofsaid patient, comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime.

In a third principal embodiment the invention provides a method oftreating early satiety resulting from cancer cachexia in a human cancerpatient comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime.

In a fourth principal embodiment the invention provides a method oftreating fatigue resulting from cancer cachexia in a human cancerpatient comprising administering to said patient a therapeuticallyeffective amount of anamorelin for a therapeutically effective period oftime. The fatigue can derive from a number of sources, includingdepression, anemia, sarcopenia, anorexia, vomiting-related malnutrition,chemo-toxicity, opioid use, or sleep disturbances, or any combination ofthe foregoing conditions.

In a fifth principal embodiment the invention provides a method ofincreasing the survival time of a terminally ill cancer patientcomprising administering to said patient a therapeutically effectiveamount of anamorelin for a therapeutically effective period of time.

In a sixth principal embodiment the invention provides a method ofimproving quality of life as measured by FAACT in the anorexia/cachexiadomain in a human cancer patient comprising administering to saidpatient a therapeutically effective amount of anamorelin for atherapeutically effective period of time.

In a seventh principal embodiment the invention provides a method ofincreasing total body mass, lean body mass, and fat mass in a humanpatient suffering from cancer cachexia comprising administering to saidpatient a therapeutically effective amount of anamorelin for atherapeutically effective period of time. The method is preferablypracticed in a patient who has lost total body mass, lean body mass, aswell as fat mass over the preceding three or six months. The patientmight have lost greater then 1, 2, 3, 4 or even 5% of total body mass,lean body mass, and fat mass, in any combination of percentages, but hasmost preferably lost greater than 2% of total body mass, lean body mass,and fat mass over the previous six months.

In an eighth principal embodiment, the invention provides a method ofimproving quality of life in a human cancer patient comprisingadministering to said patient a therapeutically effective amount ofanamorelin for a therapeutically effective period of time, wherein thequality of life improvement is measured by:

-   -   FAACT (Total Score or TOI);    -   SEA Score;    -   SEF Score;    -   FACIT-G (Total Score or TOI); or    -   FACIT-F (Total Score or TOI).

In any of the foregoing principal embodiments, the administration ispreferably oral, and the drug is preferably administered once daily.

In any of the foregoing principal embodiments, the patient has invarious subembodiments suffered in the previous three, six months ortwelve months:

-   -   anorexia, early satiety, weight loss, muscle wasting, anemia, or        oedema, or 3, 4, 5 or all of these conditions;    -   body weight loss greater than or equal to 5% and/or body mass        index less than 20 kg/m²;    -   body weight loss greater than 2, 3, 4 or 5% with a BMI <20;    -   greater than 2, 3, 4 or 5% body weight, fat and muscle loss with        a BMI <20;    -   body weight loss greater than 2, 3, 4, or 5% with an        appendicular skeletal muscle index consistent with sarcopenia        (males <7.26 kg/m²; females <5.45 kg/m²);    -   greater than 2, 3, 4 or 5% body weight, fat and muscle loss and        increased protein catabolism;    -   a reduction of 3, 4, or 5 points in FAACT, FACIT-F, FACT-G, SEF,        FAACT in the anorexia/cachexia domain, FAACT TOI, FACIT-F TOI,        or FACT-G TOI.

Any of the foregoing principal embodiments can be performed in any typeof cancer, but each of the methods is preferably practiced in a cancerof the type which is generally associated with cancer cachexia.Non-limiting examples of relevant cancers include, e.g., breast cancer,prostate cancer, multiple myeloma, transitional cell carcinoma, lungcancer (e.g., non-small cell lung cancer (NSCLC)), renal cancer, thyroidcancer and other cancers causing hyperparathyroidism, adenocarcinoma,leukemia (e.g., chronic myeloid leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, acute lymphocytic leukemia), lymphoma(e.g., B cell lymphoma, T cell lymphoma, non-Hodgkin's lymphoma,Hodgkin's lymphoma), head and neck cancer, esophageal cancer, stomachcancer, colon cancer, intestinal cancer, colorectal cancer, rectalcancer, pancreatic cancer, liver cancer, cancer of the bile duct, cancerof the gall bladder, ovarian cancer, uterine endometrial cancer, vaginalcancer, cervical cancer, bladder cancer, neuroblastoma, sarcoma,osteosarcoma, malignant melanoma, squamous cell cancer, bone cancer,including both primary bone cancers (e.g., osteosarcoma, chondrosarcoma,Ewing's sarcoma, fibrosarcoma, malignant fibrous histiocytoma,adamantinoma, giant cell tumor, and chordoma) and secondary (metastatic)bone cancers, soft tissue sarcoma, basal cell carcinoma, angiosarcoma,hemangiosarcoma, myxosarcoma, liposarcoma, osteogenic sarcoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, testicular cancer, uterinecancer, gastrointestinal cancer, mesothelioma, leiomyosarcoma,rhabdomyosarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, Waldenstroom's macroglobulinemia,papillary adenocarcinomas, cystadenocarcinoma, bronchogenic carcinoma,choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelialcarcinoma, glioma, glioblastoma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, retinoblastoma, medullarycarcinoma, thymoma, sarcoma, etc. In a preferred embodiment the canceris non-small cell lung cancer (NSCLC), more preferably non-resectableStage III or IV NSCLC.

The patient may or may not be receiving chemotherapy in any of theforegoing principal embodiments. Non-limiting examples of chemotherapyagents include anti-metabolites such as pyrimidine analogs (e.g.,5-fluorouracil [5-FU], floxuridine, capecitabine, gemcitabine andcytarabine) and purine analogs, folate antagonists and relatedinhibitors (e.g., mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (e.g.,vinblastine, vincristine, and vinorelbine), microtubule disruptors suchas taxanes (e.g., paclitaxel, docetaxel), vincristin, vinblastin,nocodazole, epothilones and navelbine, epidipodophyllotoxins (e.g.,etoposide, teniposide), DNA damaging agents (e.g., actinomycin,amsacrine, anthracyclines, bleomycin, busulfan, camptothecin,carboplatin, chlorambucil, cisplatin, nedaplatin, cyclophosphamide,cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin,aclarubicin, purarubicin, hexamethyhnelamineoxaliplatin, iphosphamide,melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea,nimustine, ranimustine, estramustine, plicamycin, procarbazine, taxol,taxotere, teniposide, triethylenethiophosphoramide and etoposide(VP16)); antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin,doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone,bleomycins, plicamycin (mithramycin), pleomycin, peplomycin, mitomycins(e.g., mitomycin C), actinomycins (e.g., actinomycin D),zinostatinstimalamer); enzymes (e.g., L-asparaginase); neocarzinostatin;antiplatelet agents; antiproliferative/antimitotic alkylating agentssuch as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide andanalogs, imidazol carboxamide, melphalan, chlorambucil, nitrogenmustard-N-oxide hydrochloride, ifosfamide), ethylenimines andmethylmelamines (e.g., hexamethylmelamine, thiotepa, carboquone,triethylene thiophospharamide), alkyl sulfonates (e.g., busulfan,isoprosulfan tosylate), nitrosoureas (e.g., carmustine (BCNU) andanalogs, streptozocin), trazenes-dacarbazinine (DTIC); epoxide typecompounds (e.g., mitobronitol); antiproliferative/antimitoticantimetabolites such as folic acid analogs (e.g., methotrexate);platinum coordination complexes (e.g., cisplatin, carboplatin,oxaliplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (e.g., estrogen, tamoxifen, goserelin,bicalutamide, nilutamide) and aromatase inhibitors (e.g., letrozole,anastrozole); anticoagulants (e.g., heparin, synthetic heparin salts andother inhibitors of thrombin); fibrinolytic agents (e.g., tissueplasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory agents;antisecretory agents (e.g., breveldin); immunosuppressives (e.g.,cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine,mycophenolate mofetil); anti-angiogenic compounds (e.g., TNP-470,genistein, bevacizumab) and growth factor inhibitors (e.g., fibroblastgrowth factor (FGF) inhibitors); angiotensin receptor blockers; nitricoxide donors; antisense oligonucleotides; antibodies (e.g.,trastuzumab); cell cycle inhibitors and differentiation inducers (e.g.,tretinoin); mTOR inhibitors, topoisomerase inhibitors (e.g., doxorubicin(adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin,eniposide, epirubicin, etoposide, idarubicin, mitoxantrone, topotecan,irinotecan); growth factor signal transduction kinase inhibitors;mitochondrial dysfunction inducers; chromatin disruptors; sobuzoxane;tretinoin; pentostatin; flutamide; porphimer natrium; fadrozole;procarbazine; aceglatone, and mitoxantrone.

In any of the foregoing principal embodiments, the therapeuticallyeffective amount of anamorelin can vary across a range of suitable dosesdepending on the health of the subject, the desired response, the dosageform and the route of administration. In a preferred subembodiment thetherapeutically effective amount is from about 10 to about 500 mg/day ofanamorelin, preferably from 25 to 300 mg/day, more preferably 50 to 150mg/day. In an even more preferred embodiment the dose is administered asa single administration once per day, preferably before the first mealof the day.

In any of the foregoing principal embodiments, the therapeuticallyeffective amount of anamorelin is preferably effective to increase leanbody mass in said patient, or to increase the total body mass and leanbody mass of the patient, or to increase the total body weight, leanbody mass and fat mass of the patient.

A particularly surprising aspect of any of the foregoing principalembodiments is the sustainability of the effect observed in cancerpatients, which is reflected in the therapeutically effective period ofadministration. This sustainability can be observed in patients havingany ECOG score, including an ECOG score greater than about 2.0, 2.5, 3,3.5 or 4. In any of the foregoing embodiments the therapeuticallyeffective period of time is preferably twelve weeks. In alternativeembodiments, the therapeutically effective period is 3, 6, 9, 12, 13,15, 18, 21 or 24 weeks, or any range defined by these endpoints, such as13 to 24 weeks. When a particular period of time is given, it will beunderstood that anamorelin can be administered for a greater period oftime, as long as the required response is observed during the periodgiven. It will further be understood that the response to treatment canbe observed beyond the prescribed period. I.e., administration for 12weeks includes administration for at least 12 weeks, and treatment for12 weeks means treatment for at least 12 weeks.

The treatment effect in any of the foregoing principal embodiments canbe correlated or not correlated with IGF-1 levels and/or IGFBP-3 levels.In one embodiment for any of the foregoing methods the treatment effectis not correlated with increases in IGF-1 levels. In another embodimentthe treatment effect is not correlated with increases in IGFBP-3 levels.

Any of the foregoing principal embodiments can be practiced based on thepatient's ECOG status. Thus, for example, any of the embodiments can bepracticed in a patient having a performance status on the ECOG scale of2, 2.5, 3, 4 or higher, i.e. from 2 to 4, or 2, 3 or 4.

Any of the foregoing principal embodiments may also be practiced basedon age. Thus, for example, any of the foregoing methods may be practicedin an individual greater than 50, 55, 60, 65 or 70 years of age. In oneparticular embodiment the invention is practiced in a population ofpatients ranging from 50 to 90, who in one embodiment are suffering fromlung cancer.

Any of the foregoing principal embodiments may further be divided basedon BMI status. Thus, for example, any of the foregoing methods may bepracticed in an individual having a BMI less than 22, 20, 19, 18.5 oreven 18. Alternatively, any of the foregoing embodiments may bepracticed in an individual having a BMI greater than 14, 16, 18 or 20.

Any of the foregoing embodiments may also be limited based on otherparameters. Thus, in any of the foregoing principal embodiments thecancer can be defined by a squamous tumor histology. In any of theforegoing principal embodiments the patient's cancer may or may not havemetasticized. In any of the foregoing principal embodiments the patientmay or may not be receiving chemotherapy and/or radiotherapy. In any ofthe foregoing principal embodiments the patient may or may not bereceiving opioids.

Dosage Forms/Routes of Administration

Pharmaceutical compositions for preventing and/or treating a subject arefurther provided comprising a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt or adductthereof, and one or more pharmaceutically acceptable excipients.

A “pharmaceutically acceptable” excipient is one that is notbiologically or otherwise undesirable, i.e., the material can beadministered to a subject without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of the othercomponents of the pharmaceutical composition in which it is contained.The carrier can be selected to minimize any degradation of the activeingredient and to minimize any adverse side effects in the subject, aswould be well known to one of skill in the art. The carrier can be asolid, a liquid, or both.

The disclosed compounds can be administered by any suitable route,preferably in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment or prevention intended.The active compounds and compositions, for example, can be administeredorally, rectally, parenterally, ocularly, inhalationaly, or topically.In particular, administration can be epicutaneous, inhalational, enema,conjunctival, eye drops, ear drops, alveolar, nasal, intranasal,vaginal, intravaginal, transvaginal, ocular, intraocular, transocular,enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal,transrectal, injection, infusion, intravenous, intraarterial,intramuscular, intracerebral, intraventricular, intracerebroventricular,intracardiac, subcutaneous, intraosseous, intradermal, intrathecal,intraperitoneal, intravesical, intracavernosal, intramedullar,intraocular, intracranial, transdermal, transmucosal, transnasal,inhalational, intracisternal, epidural, peridural, intravitreal, etc.

EXAMPLES

The following two studies were conducted to evaluate the effect ofanamorelin on LBM in patients with NSCLC, as well as to determine itseffects on body weight, patient concerns regarding cachexia and fatigue,and overall survival. Efforts have been made to ensure accuracy withrespect to numbers (e.g., amounts, temperature, etc.) but some errorsand deviations should be accounted for. The following examples are putforth so as to provide those of ordinary skill in the art with acomplete disclosure and description of how the methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention.

Example 1 Anamorelin HCl in the Treatment of Non-Small Cell LungCancer—Cachexia (NSCLC-C): A Randomized, Double-Blind,Placebo-Controlled, Multicenter, Phase III Study to Evaluate the Safetyand Efficacy of Anamorelin HCl in Patients with NSCLC-C (Romana 1)

Key features of the Romana 1 study are as follows:

-   -   DESIGN: randomized, double-blind, placebo-controlled,        multicenter, phase 3 study to evaluate the safety and efficacy        of anamorelin HCl (anamorelin) in patients with NSCLC-Cachexia        (59 sites; 15 countries)    -   PRIMARY ENDPOINT: Lean body mass (LBM) by DXA    -   SECONDARY ENDPOINTS:        -   Key: pooled overall survival, Anorexia/Cachexia sub-domain,            Fatigue sub-domain, Simplified Evaluation of Appetite (SEA),            and Simplified Evaluation of Fatigue (SEF)        -   Other: Body weight, study specific overall survival,            FAACT/FACIT-F trial outcome index (TOI) and total scores,            additional LBM analyses    -   EXPLORATORY ENDPOINTS: Hunger Assessment Scale (HAS), Karnofsky        (KPS), responder analyses; Population pharmacokinetics (PK) in        90 patients    -   STUDY POPULATION: advanced NSCLC (unresectable Stage III or IV)        and cachexia (≥5% body weight within 6 months or screening        BMI<20 kg/m²)    -   SAMPLE SIZE: 484 patients; randomization ratio 2:1        (anamorelin:placebo)    -   DOSING: placebo or 100 mg anamorelin for 12 weeks    -   SAFETY ASSESSMENTS: Adverse events (AEs), labs, vitals, ECGs

FIG. 1 is a graphical representation of the results of the primaryefficacy study (lean body mass), particularly the median change frombaseline in the ITT population. Panel A depicts changes in LBM inpatients receiving placebo (PBO) vs. anamorelin over the 12-week studyperiod. Patients receiving anamorelin showed higher increases in LBMrelative to patients receiving placebo.

TABLE 1 Analysis of Change from Baseline Over 12 Weeks in Lean BodyMass - ITT Population. Lean Body Mass 100 mg Placebo anamorelin (N =161) (N = 323) N* 158 316 Median −0.44 1.10 95% CI (−0.88, 0.20) (0.76,1.42) Median 1.54 P-value** <0.0001 *Sample size takes into accountthose who were excluded due to missing baseline values and/or missingdeath dates. **P-value is obtained from Wilcoxon Rank-sum test, takinginto account missing post-baseline values (i.e., imputation), wherebylower ranks represent worse outcomes. The ranking order is determined bythe average change from baseline in LBM at Week 6 and Week 12 withimputed values, and also by the survival date.

As shown in Table 1 above, for LBM, there were statistically significant(based on unadjusted p-values) effects favoring anamorelin. This is trueamong all subgroups except for age >65, BMI<18.5, ECOG 2 and female,which may be due to small sample size in these subgroups.

Key secondary endpoints were measured in the MITT population, with abrief summary of results as follows. These results are further explainedand demonstrated in the following Figures and Tables.

In terms of health-related quality of life measurements (HR-QoL),results from the anorexia/cachexia domain of the FAACT assessment showedanamorelin provides statistically significant and clinically meaningfulimprovements in patient concerns related to these issues. Patients inthe anamorelin group also had statistically significant and clinicallymeaningful improvements in regard to the SEA assessment, which focuseson feelings of early satiety, appetite, food consumption, and pressureby others to eat. HR-QoL assessments related to fatigue, listlessnessand weakness, as measured by the Fatigue domain of FACIT-F, showedstatistically significant improvements at Weeks 9 and 12. Some subgroupsshowed a trend of improvement in the FACIT-F assessment with anamorelintreatment. There was an overall trend of improvement in the SEFassessment, which focuses on feelings of fatigue and general weakness.Patients in some subgroups also had trends of improvement in regard tothe SEF assessment.

FIGS. 2A-B are graphical representations of patient symptoms andconcerns related to cachexia as measured by FAACT anorexia/cachexiasubscore and SEA score, specifically the treatment comparison of changefrom baseline at each visit in the MITT population. Panel A shows theresults for the anorexia/cachexia domain of FAACT in the MITT populationover the 12-week study period, including the statistical significance ofany differences in results from patients treated with placebo vs.anamorelin (p values). Patients in the anamorelin group showedstatistically significant and clinically meaningful improvements in QoLrelated to concerns over cachexia. Panel B shows the results for the SEAscore of FAACT in the MITT population over the 12-week study period,including the statistical significance of any differences in resultsfrom patients treated with placebo vs. anamorelin (p values). Patientsin the anamorelin group showed statistically significant and clinicallymeaningful improvements in QoL concerns measured by the SEA, such asimprovements in general appetite and consuming sufficient amounts offood, and decreases in early satiety and pressure by others to eat.Results are also presented below in Table 2. Data shown are from amixed-effects pattern-mixture model.

TABLE 2 Analysis of Change in Patient Symptoms and Concerns Related toAnorexia/Cachexia from Baseline Over 12 Weeks - MITT Population.Anorexia/Cachexia Domain SEA Score 100 mg 100 mg Placebo anamorelinPlacebo anamorelin (N = 141) (N = 284) (N = 141) (N = 284) N 141 282 140281 LS Mean (SE) 1.92 (0.805) 4.12 (0.752) 0.92 (0.339) 1.57 (0.317)Treatment Difference (anamorelin vs. placebo) LS Mean (SE) 2.21 (0.617)0.65 (0.262) 95% CI (0.99, 3.42) (0.14, 1.16) P-value 0.0004 0.0134 *Note, importance difference is estimated to be ~3 points foranorexia/cachexia domain and ~1 point for SEA score, and both were metwith anamorelin treatment.

FIGS. 3A-B are graphical representations of patient symptoms andconcerns related to fatigue as measured by FACIT-F fatigue subscore andSEF score, specifically the treatment comparison of change from baselineat each visit in the MITT population. Panel A represents the results forthe Fatigue Domain of FACIT-F assessment over the 12-week study periodin MITT patients, including the statistical significance of anydifferences in results from patients treated with placebo vs.anamorelin. As can be seen in this panel, statistically significantimprovements in the assessment were present at Weeks 9 and 12 inanamorelin patients versus those on placebo. Subgroups of interestreceiving anamorelin showed trends of improvement in their fatiguelevels. Panel B represents the results for the SEF score of FACIT-Fassessment over the 12-week study period in MITT patients, including thestatistical significance of any differences in results from patientstreated with placebo vs. anamorelin. Here, there was an overall smalltrend of improvement among anamorelin patients in terms of lowerfatigue, lower overall feelings of weakness, and lower amounts of timespent in bed; subgroups showed these trends of improvement as well.Results are also presented in Table 3 below, and specific findings forsubgroups are also presented below. Data shown in FIGS. 3A-B are from amixed-effects pattern-mixture model.

TABLE 3 Patient Symptoms and Concerns Related to Fatigue - Analysis ofChange from Baseline Over 12 Weeks in MITT Population. Fatigue DomainSEF Score 100 mg 100 mg Placebo anamorelin Placebo anamorelin (N = 141)(N = 284) (N = 141) (N = 284) N 141 282 139 280 LS Mean (SE) −1.91 0.26−0.23 0.11 (0.933) (0.886) (0.325) (0.309) Treatment Difference(anamorelin vs. placebo) LS Mean (SE) 1.45 (0.752) 0.33 (0.265) 95% CI(−0.02, 2.93) (−0.19, 0.85) P-value 0.0537 0.2098

Subgroup analyses of the above data regarding the change from baselinein Fatigue Domain of FACIT-F in the MITT population shows a trend ofimprovement in subgroups. Specific trends included the followingsubgroups. In a subgroup of patients aged 65 years and younger withconcomitant opioid use and ECOG 2 (at Weeks 9 and 12), and BMI≤18.5improvement at Week 3, 6 and at Week 9, 12 patients showed statisticallysignificant improvement.

In addition, the following subgroup trends were also observed: 1) amongpatients with no-concomitant opioid use, a smaller overall improvementtrend was noted; 2) among patients with ECOG 0-1, a gap increase betweenplacebo and anamorelin through Week 3, 6, 9 to 12 was noted; 3) amongpatients with BMI>18.5, there was a smaller improvement trend from Week3 to 12; and 4) a general improvement trend in males from Week 3 to 6was seen (the improvement was statistically significant at Week 9, witha borderline change at Week 12).

Subgroup analyses of the above data regarding the change from baselinein Simplified Evaluation of Fatigue (SEF) in the MITT population show anoverall small trend of improvement in subgroups in terms of fatigue andoverall weakness. The following subgroup trends were observed: 1)concomitant opioid use showed a small trend of improvement; and 2)patients with BMI≤18.5 showed improvement trend over 12 Weeks(statistically significant at Week 3 and 6).

Other secondary endpoints measured in the MITT population, along withresults, included the following:

Body Weight: Statistically significant and clinically meaningfulimprovements were seen in anamorelin patients versus those receivingplacebo.

Other LBM Analyses: Percentage change from baseline in LBM weremeasured, with LBM showing consistent improvement throughout the 12-weekstudy.

Other FAACT/FACIT-F Analyses: FAACT TOI and total score showedstatistically significant and clinically meaningful improvements forTOI, with a trending benefit for the total score among the anamorelinpatients. This indicates that anamorelin treatment improves patientconcerns over appetite, food consumption, early satiety, and pain orvomiting. The FACIT-F TOI and total score also showed a trending benefitamong the anamorelin patients. Such improvement indicates thatanamorelin treatment improves patient concerns in regard to fatigue andweakness. Overall Survival: Study-specific overall survival-Datapending.

FIG. 4 is a graphical representation of the change from baseline overtime in body weight in the MITT population, including the statisticalsignificance of any differences in results from patients treated withplacebo vs. anamorelin. Over the course of the study, patients treatedwith anamorelin showed a greater, statistically significant increase inbody weight versus patients in the placebo group; the results are alsopresented in Table 4 below. Data shown are from a mixed-effectspattern-mixture model.

TABLE 4 Analysis of Change in Body Weight Over 12 Weeks - MITTPopulation. Placebo 100 mg anamorelin Overall Change from Baseline (N =141) (N = 284) N 141 283 LS Mean (SE) 0.14 (0.363) 2.20 (0.326)Treatment Difference (anamorelin vs. placebo) LS Mean (SE) 2.07 (0.325)95% CI (1.43, 2.70) P-value <0.0001

FIGS. 5A-B are graphical representations of health-related Quality ofLife changes from baseline in FAACT Total and TOI (Total Outcome Index)in the MITT population. Panel A represents the results for the FAACTTotal assessment over the 12-week study period in MITT patients,including the statistical significance of any differences in resultsfrom patients treated with placebo vs. anamorelin (p-values). Theoverall treatment difference for the FACCT Total was 2.67±1.459;p=0.0673. Panel B represents the results for the FAACT TOI assessmentover the 12-week study period in MITT patients, including thestatistical significance of any differences in results from patientstreated with placebo vs. anamorelin (p-values). The overall treatmentdifference for the FAACT TOI assessment was 2.86±1.161; p=0.0140. Asmentioned above, FAACT TOI showed statistically significant andclinically meaningful improvements, and there was a trending benefit forthe total score among the anamorelin patients, indicating thatanamorelin treatment improves patient concerns over appetite, foodconsumption, early satiety, and pain or vomiting. Data shown are from amixed-effects pattern-mixture model.

FIGS. 6A-B are graphical representations of health-related Quality ofLife change from baseline in FACIT Total and TOI (Total Outcome Index)in the MITT population. Panel A represents the results for the FACITTotal assessment over the 12-week study period in MITT patients,including the statistical significance of any differences in resultsfrom patients treated with placebo vs. anamorelin (p-values). Theoverall treatment difference for the FACIT Total was 2.07±1.651;p=0.2100. Panel B represents the results for the FACIT TOI assessmentover the 12-week study period in MITT patients, including thestatistical significance of any differences in results from patientstreated with placebo vs. anamorelin (p-values). The overall treatmentdifference for the FACIT TOI assessment was 1.90±1.358; p=0.1615. Asmentioned above, the FACIT-F Total and TOI showed a trending benefitamong the anamorelin patients. Such improvement indicates thatanamorelin treatment improves patient concerns in regard to fatigue andweakness. Data shown are from a mixed-effects pattern-mixture model.

The Romana 1 study yielded the following overall conclusions regardingefficacy of anamorelin treatment. Baseline demographics were balanced(N=484). Overall, median age=62 yr, male (76%), ECOG=2 (18.6%),metastatic (76.4%), and prior weight loss >10% (39.5%). Over 12 weeks,anamorelin significantly increased LBM with respect to placebo (medianchange from baseline of 1.10 kg [95% CI 0.76, 1.42] vs. −0.44 kg [95% CI−0.88, 0.20]; p<0.0001). Increases in lean body mass (LBM) was found tobe statistically significant (p<0.0001).

In terms of secondary efficacy, body weight was significantly increasedin patients who received anamorelin versus those on placebo (2.20±0.3vs. 0.14±0.4 kg; p<0.0001). The FAACT assessment trial outcome index(TOI), anorexia/cachexia domain and Simplified Evaluation of Appetite(SEA) scores, which measured changes in appetite, early satiety, andfood consumption, were significantly increased and exceeded minimallyimportant difference thresholds, while total scores showed trendingbenefits for patients receiving anamorelin versus those in the placebogroup. The FACIT-F assessment fatigue domain was statisticallysignificant at Weeks 9 and 12; Simplified Evaluation of Fatigue (SEF),TOI and total scores were not statistically different from placebo, butgeneral trends of improvement with anamorelin were noted. Specifically,patient symptoms and concerns regarding fatigue and weakness appeared tostabilize in the anamorelin arm and worsen in the placebo arm over time,attaining statistically significant differences in FACIT-F scores atweek 9 (0.33±0.9 vs. −1.50±1.0; p=0.0331) and week 12 (0.48±1.0 vs.−2.10±1.0; p=0.0244). Over the entire 12 week treatment period, thedifference between treatments did not reach statistical significance(1.45+0.8; p=0.0537); the trend favored anamorelin. FAACT scoressignificantly improved over 12 weeks in anamorelin vs. placebo arms(FAACT scores of 4.12±0.8 vs. 1.92±0.8; p=0.0004).

Trends of improvement in specific patient subgroups include: 1) age lessthan 65 years; 2) concomitant opioid use; 3) ECOG 2 at Week 9, 12; and4) BMI<18.5.

Overall, the study shows that anamorelin treatment for 12 weeks was welltolerated, and that the anamorelin therapy increased LBM and body weightwhile reducing CACS symptoms/concerns in advanced NSCLC patients withcachexia. These increases were highly statistically significant, andappeared to continue to increase with longer exposure. Anamorelin alsostabilized patient symptoms/concerns related to fatigue over the 12weeks of treatment in addition to a statistically significant treatmentdifference in fatigue symptoms/concerns at weeks 9 and 12.

Example 2 Anamorelin HCl in the Treatment of Non-Small Cell LungCancer—Cachexia (NSCLC-C): A Randomized, Double-Blind,Placebo-Controlled, Multicenter, Phase III Study to Evaluate the Safetyand Efficacy of Anamorelin HCl in Patients with NSCLC-C (Romana 2)

Key features of the Romana 2 study are as follows:

-   -   DESIGN: randomized, double-blind, placebo-controlled,        multicenter, phase 3 study to evaluate the safety and efficacy        of anamorelin HCl (anamorelin) in patients with NSCLC-Cachexia        (59 sites; 15 countries)    -   PRIMARY ENDPOINT: Lean body mass (LBM) by DXA    -   SECONDARY ENDPOINTS:        -   Key: pooled overall survival, Anorexia/Cachexia sub-domain,            Fatigue sub-domain, Simplified Evaluation of Appetite (SEA),            and Simplified Evaluation of Fatigue (SEF)        -   Other: Body weight, study specific overall survival,            FAACT/FACIT-F trial outcome index (TOI) and total scores,            additional LBM analyses    -   EXPLORATORY ENDPOINTS: Hunger Assessment Scale (HAS), Karnofsky        (KPS), responder analyses; Population pharmacokinetics (PK) in        90 patients    -   STUDY POPULATION: advanced NSCLC (unresectable Stage III or IV)        and cachexia (≥5% body weight within 6 months or screening        BMI<20 kg/m²)    -   SAMPLE SIZE: 495 patients; randomization ratio 2:1        (anamorelin:placebo)    -   DOSING: placebo or 100 mg anamorelin for 12 weeks    -   SAFETY ASSESSMENTS: Adverse events (AEs), labs, vitals, ECGs

FIG. 7 is a graphical representations of the results of a primaryefficacy study (lean body mass), particularly the median change frombaseline in the ITT population with regard to these endpoints. Thefigure depicts changes in LBM in patients receiving placebo (PBO) vs.anamorelin over the 12-week study period. Patients receiving anamorelinshowed higher increases in LBM relative to patients receiving placebo.These results are also represented in Table 5 below.

TABLE 5 Analysis of Change from Baseline Over 12 Weeks in Lean BodyMass - ITT Population. Lean Body Mass 100 mg Placebo anamorelin (N =165) (N = 330) N* 157 321 Median −0.96 0.75 95% CI −1.27, −0.46 0.51,1.00 Treatment Difference (anamorelin vs. placebo) Median 1.71 P-value**<0.0001 *Sample size takes into account those who were excluded due tomissing baseline values and/or missing death dates. **P-value isobtained from Wilcoxon Rank-sum test, taking into account missingpost-baseline values (i.e., imputation), whereby lower ranks representworse outcomes. The ranking order is determined by the average changefrom baseline in LBM at Week 6 and Week 12 with imputed values, and alsoby the survival date.

As shown in FIG. 7 and Table 5 above, anamorelin patients showed ahighly statistically significant improvement in lean body mass (LBM).This was true for all subgroups except those patients with a BMI≤18.5(which may be due to a very small sample size of this subgroup).

Key secondary endpoints were measured in the MITT population, with abrief summary of results as follows. These results are further detailedin the following Figures and Tables.

In terms of health-related quality of life measurements (HR-QoL),results from the anorexia/cachexia domain of the FAACT assessment showedanamorelin provides statistically significant and clinically meaningfulimprovements in patient concerns related to these issues. Patients inthe anamorelin group also had statistically significant and clinicallymeaningful improvements in regard to the SEA assessment, which focuseson feelings of early satiety, appetite, food consumption, and pressureby others to eat. HR-QoL assessments related to fatigue, listlessnessand weakness, as measured by the Fatigue domain of FACIT-F, showedtrends of improvement in specific subgroups who received anamorelintreatment, such as those aged 65 years and younger, patients withconcomitant opioid use, patients with an ECOG of 2, and patients with aBMI≤18.5. Patients in some subgroups, specifically patients withconcomitant opioid use and patients with a BMI≤18.5, also had trends ofimprovement in regard to the SEF assessment, which focuses on feelingsof fatigue and general weakness.

FIGS. 8A-B are graphical representations of patient symptoms andconcerns related to cachexia as measured by FAACT anorexia/cachexiasubscore and SEA score, specifically the treatment comparison of changefrom baseline at each visit in the MITT population, including thestatistical significance of any differences in results from patientstreated with placebo vs. anamorelin (p-values). Panel A shows theresults for the anorexia/cachexia domain of FAACT in the MITT populationover the 12-week study period, including the statistical significance ofany differences in results from patients treated with placebo vs.anamorelin (p values). Patients in the anamorelin group showedstatistically significant and clinically meaningful improvements in QoLrelated to concerns over cachexia. Panel B shows the results for the SEAscore of FAACT in the MITT population over the 12-week study period,including the statistical significance of any differences in resultsfrom patients treated with placebo vs. anamorelin (p values). Patientsin the anamorelin group showed statistically significant and clinicallymeaningful improvements in QoL concerns measured by the SEA, such asimprovements in general appetite and consuming sufficient amounts offood, and decreases in early satiety and pressure by others to eat.Results are also presented below in Table 6. Data shown are from amixed-effects pattern-mixture model.

TABLE 6 Analysis of Change from Baseline in HR-QoL Scores Over 12Weeks - MITT Population. Anorexia/Cachexia Domain SEA Score 100 mg 100mg Placebo anamorelin Placebo anamorelin (N = 136) (N = 268) (N = 136)(N = 268) N 133 266 133 266 LS Mean (SE) 1.34 (1.032) 3.48 (0.944) 0.41(0.435) 1.08 (0.400) Treatment Difference (anamorelin vs. placebo) LSMean (SE) 2.14 (0.676) 0.66 (0.283) 95% CI (0.81, 3.47) (0.11, 1.22)P-value 0.0016 0.0192 * Note that the minimally important difference(MID) is ~3 points for anorexia/cachexia domain and ~1 point for SEAscore, and both were met with anamorelin treatment for each.

FIGS. 9A-B are graphical representations of patient symptoms andconcerns related to fatigue as measured by FACIT-F fatigue subscore andSEF score, specifically the treatment comparison of change from baselineat each visit in the MITT population, including the statisticalsignificance of any differences in results from patients treated withplacebo vs. anamorelin (p-values). Panel A represents the results forthe Fatigue Domain of FACIT-F assessment over the 12-week study periodin MITT patients, including the statistical significance of anydifferences in results from patients treated with placebo vs.anamorelin. As can be seen in this panel, statistically significantimprovements in the assessment were present in anamorelin patientsversus those on placebo. Subgroups of interest receiving anamorelinshowed trends of improvement in their fatigue levels; further details onthese subgroups appear below and in FIGS. 10A-D (further describedbelow). Panel B represents the results for the SEF score of FACIT-Fassessment over the 12-week study period in MITT patients, including thestatistical significance of any differences in results from patientstreated with placebo vs. anamorelin. Here, there was an overall smalltrend of improvement among anamorelin patients in terms of lowerfatigue, lower overall feelings of weakness, and lower amounts of timespent in bed; subgroups showed these trends of improvement as well.Specific improvements were noted in subgroups of patients withconcomitant opioid use and patients with a BMI≤18.5. Data shown in FIGS.10A-D are from a mixed-effects pattern-mixture model.

FIGS. 10A-D are graphical representations of the results for the FatigueDomain of FACIT-F assessment over the 12-week study period in specificsubgroups of MITT patients. Each of these subgroups showed improvementin the assessment among anamorelin patients relative to those patientsin the placebo group. Panel A shows the improvement in FACIT-F fatiguescore over the study period in patients under the age of 65; while therewas some decrease in the fatigue score after Week 3, those patients inthe treatment subgroup did not experience as severe of a decline inscore as those in the placebo group, indicating improved fatigueassessment (i.e., less fatigue and/or weakness) due to the anamorelintreatment. Panel B shows the results of the FACIT-F fatigue score inpatients who were concomitantly taking opioids; again, while there wassome decrease in the score after Week 3, patients taking anamorelin didnot experience as severe of a decline in score as those in the placebogroup, again indicating that anamorelin treatment results in improvedfatigue assessment (i.e., less fatigue and/or weakness) in thissubgroup. Panel C represents score results from patients with an ECOG of2. In this subgroup, anamorelin treatment provided a general trend ofimprovement in the FACIT-F score, indicating that these patients hadless fatigue and/or weakness relative to those in the placebo group.Panel D shows the FACIT-F fatigue score in patients with a BMI less thanor equal to 18.5. Patients in this subgroup who were in the anamorelingroup maintained a steady score after Week 3, while those in the placebogroup had a steady decline in score over these weeks, suggesting thatpatients in the anamorelin group had less fatigue and/or weaknessrelative to those in the placebo group.

Key secondary endpoints in the MITT population, along with a briefstatement of results of the endpoints, are summarized below. FIG. 11 andTable 9 below provide further data on body weight changes in thispopulation.

Statistically significant and clinically meaningful improvements in bodyweight were seen in anamorelin patients relative to those taking placeboin the MITT population. In addition, a consistent improvement in LBM ofanamorelin patients was seen. Finally, patients in the anamorelin groupshowed a trending benefit in cachexia concerns according to changes inthe FAACT TOI and total score. No benefit of anamorelin was seen inFACIT-F TOI and total score.

FIG. 11 is a graphical representation of the change from baseline inbody weight of the MITT population over the course of the study,including the statistical significance of any differences in resultsfrom patients treated with placebo vs. anamorelin (p-values). Patientsin the anamorelin group experienced a statistically significant increasein body weight over the 12-week study, with the majority of the weightgain occurring by Week 3. Weight gain was maintained in the anamorelingroup. The patients in the placebo group had a general decreasing trendof weight gain.

TABLE 7 Analysis of Change in Body Weight Over 12 Weeks - MITTPopulation. Overall Placebo 100 mg anamorelin Change from Baseline (N =136) (N = 268) N 135 267 LS Mean (SE) −0.57 (0.438) 0.95 (0.386)Treatment Difference (anamorelin vs. placebo) LS Mean (SE) 1.53 (0.327)95% CI (0.89, 2.17) P-value <0.0001 * Note: body weight may continue toincrease with continued treatment past 12 weeks (i.e., observed meanvalues for change from baseline to Week 3, 6, 9, and 12 for anamorelinwas 1.11 kg, 1.37 kg, 1.76 kg, and 1.91 kg, respectively).

Overall, the Romana 2 study found that the primary efficacy endpoint ofLBM showed a statistically significant increase (p<0.0001) in patientsin the anamorelin group relative to patients receiving placebo.

Health-related quality of life assessments showed that anamorelintreatment resulted in improved quality of life. The FAACT assessmentanorexia/cachexia domain and Simplified Evaluation of Appetite (SEA)scores, which measured changes in appetite, early satiety, and foodconsumption, were significantly increased and exceeded minimallyimportant difference thresholds, while FAACT TOI and total scores showedtrending benefits for patients receiving anamorelin versus those in theplacebo group. Moreover, patients in the anamorelin treatment groupdemonstrated anorexia-cachexia-related improvements (based on FAACTassessment) and enhanced appetites (based on SEA assessment) that werestatistically significant and medically meaningful. The FACIT-Fassessment fatigue domain and Simplified Evaluation of Fatigue (SEF),TOI and total scores were not statistically different from placebo, butgeneral trends of improvement in some subgroups with anamorelintreatment were noted. Specifically, improvements in fatigue were seen inpatients aged 65 years and younger, patients with concomitant opioiduse, patients with ECOG of 2, and patients with a BMI≤18.5.

Consistent with absolute changes from baseline in LBM described above,measures of the percentage of change in LBM also shows consistentincreases in anamorelin patients and decreases in placebo patients.

FIGS. 13 a and 13 b show the change from baseline over time inindividual questions from the FAACT, early satiety, in Romana 1 and 2,respectively. Symptoms of early satiety and appetite showed animprovement in the anamorelin arm in Romana 2. Romana 2 alsodemonstrated an improvement in concerns related to weight and bodyimage.

Overall, the Romana 2 study shows that anamorelin treatment for 12 weekswas well tolerated, and that the anamorelin therapy increased LBM andbody weight while reducing CACS symptoms/concerns in advanced NSCLCpatients with cachexia. These increases were highly statisticallysignificant, and appeared to continue to increase with longer exposure.Some subgroups experienced improvements in fatigue assessments.

Throughout this application, various publications are referenced, Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

The invention claimed is:
 1. A method of treating cachexia in a humanpatient having a body mass index less than 20 kg/m², comprisingadministering to the patient a therapeutically effective amount ofanamorelin once daily for a therapeutically effective period of time. 2.A method of treating cachexia in a human patient having a body massindex less than 20 kg//m², comprising administering to the patient atherapeutically effective amount of anamorelin once daily for atherapeutically effective period of time and increasing total body massof the patient.
 3. A method of treating cachexia in a human patienthaving a body mass index less than 20 kg/m², comprising administering tothe patient a therapeutically effective amount of anamorelin on a dailybasis for a therapeutically effective period of time and improvingquality of life in the patient as measured by FAACT in theanorexia/cachexia domain.
 4. A method of treating cachexia in a humanpatient having a body mass index less than 20 kg/m², comprisingadministering to the patient a therapeutically effective amount ofanamorelin once daily for a therapeutically effective period of time,increasing total body mass of the patient, and improving quality of lifein the patient as measured by a subset of symptoms questions on FAACT inthe anorexia/cachexia domain.
 5. The method of claim 1, wherein thepatient has a body weight loss greater than or equal to 2% in theprevious 6 months.
 6. The method of claim 1, further comprisingincreasing total body mass of the patient.
 7. The method of claim 1,further comprising improving quality of life in the patient as measuredby FAACT in the anorexia/cachexia domain.
 8. The method of claim 1,further comprising increasing total body mass of the patient andimproving quality of life in the patient as measured by FAACT in theanorexia/cachexia domain.
 9. The method of claim 2, wherein the patienthas a body weight loss greater than or equal to 2% in the previous 6months.
 10. The method of claim 2, further comprising improving qualityof life in the patient as measured by FAACT in the anorexia/cachexiadomain.
 11. The method of claim 3, wherein the patient has a body weightloss greater than or equal to 2% in the previous 6 months.
 12. Themethod of claim 4, wherein the patient has a body weight loss greaterthan or equal to 2% in the previous 6 months.